A phase 1 dose-escalation study to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamic activity of cln-619 (Anti-MICA/B antibody) alone and in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Judy S. Wang, Martin Gutierrez, Drew W. Rasco, Ignacio Melero Bermejo, John D. Powderly, Erika P. Hamilton, Michael Millward, Ana Maria Arance, Rafal Stec, Victor Moreno, Manish Sharma, Iwona A. Lugowska, Mark J. Shackleton, Sophia Frentzas, John Edward Janik, Tracy Liu, Irina Shapiro, Kerry Whalen, Jeffrey Alan Jones, Alexander I. Spira
Journal: Journal of Clinical Oncology (2023)

2532 Background: MICA and MICB are stress-induced ligands upregulated on the majority of human tumors. Engagement of MICA/B by the activating receptor NKG2D on NK cells and several subsets of T cells results in immune-mediated target cell lysis. However, proteases in the tumor microenvironment cleave cell surface MICA/B, enabling immune evasion. CLN-619 is a humanized MICA/B-specific IgG1 monoclonal antibody designed to prevent the proteolytic release of MICA/B, restoring immune-mediated tumor cell lysis. CLN-619 is expected to have broad anti-tumor activity. Methods: This phase 1, multicenter, open-label, first-in-human dose-escalation study (NCT05117476) enrolls patients (pts) with advanced solid tumors who progressed on available therapies, were intolerant to treatment, or refused noncurative standard treatment. CLN-619 alone (dose levels (DL) of 0.1, 0.3, 1, 3, 6, 10mg/kg) were administered intravenously every three weeks. Corticosteroid pre-medication for infusion related reaction (IRR) prophylaxis were required starting at the 3 mg/kg DL. A parallel dose-escalation is exploring CLN-619 (DL 1.0 mg/kg and higher) in combination with pembrolizumab. Response (RECIST 1.1) is assessed every 9 weeks. Data from the monotherapy dose escalation are described. Results: As of Dec 2, 2022, 23 pts (median age, 63 y, range 47-83) were enrolled, 48% were male and 61% had ECOG PS 1. Major tumor types included colon (4), cervical (3), lung (3) and prostate (3). All pts received prior systemic therapy (median 3, range 1-7); 12 patients had prior checkpoint inhibitor. The median number of CLN-619 cycles received was 2 (range, 0–8). Treatment-emergent adverse events (TEAEs) in ≥20% of pts were abdominal pain (26%), nausea (22%), pyrexia (22%), and infusion related reaction (IRR) (22%). IRRs occurred at dose levels of 0.3 mg/kg and higher. All IRR occurred in Cycle 1 and resolved within 3 hours of onset. One case of Gr3 laryngeal edema occurred at the 10 mg/kg DL in the absence of required steroid premedication and led to dose discontinuation. No fatal TEAEs were reported. A nearly dose-proportional increase in CLN-619 exposure was observed between the 0.1 mg/kg and 10 mg/kg dose levels. CLN-619 half-life ranged from 87.6 to 307 hours for DL ranging from 0.1 mg/kg to 6 mg/kg. There was one confirmed complete response in a patient with recurrent salivary gland tumor who progressed following a complete response on a PD-1 blocking agent. Another patient with cervical cancer maintained SD for 9 cycles before progressing. Conclusions: CLN-619 therapy was well tolerated at doses ranging from 0.1 to 10 mg/kg and demonstrated monotherapy clinical activity, including objective response in a patient progressing after PD-1. Updated data from the dose-escalation portion of the trial will be presented. Clinical trial information: NCT05117476 .